CH654007A5 - 9-BROMINE INDOLOCHINOLIZIN DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF. - Google Patents

Description

The invention relates to 9-bromo-indoloquinolizine derivatives and processes for their preparation. The indoloquinolizine derivatives have interesting physiological activity per se and are useful intermediates in the preparation of 10-bromo-vinaminic acid esters which, as described in published GB-A 2 036 732, can be used to treat behavioral disorders.

The present invention accordingly relates to a compound of the formula I.

25th

30th

(I),

wherein R2 is an alkyl group having 1 to 6 carbon atoms and B is hydrogen or a group of the formula R3OOC-CH2CH2-, where R3 is an alkyl group having 1 to 6 carbon atoms and either D and E together represent a carbon-nitrogen bond, the positively charged nitrogen is stabilized by an acid anion or the anion OR5, where R5 stands for an alkyl group with 1 to 6 carbon atoms or, if B does not stand for hydrogen, D can also stand for hydrogen and E for a lone pair of electrons; with the proviso that when B is hydrogen, D and E together are a carbon-nitrogen bond, the positively charged nitrogen atom of which is stabilized by an acid anion and R3 is hydrogen when D is a hydrogen atom and E is an electron pair; where the compounds of the formula I, when B is hydrogen, as the free base, when B is not hydrogen and D and E together are a carbon-nitrogen bond, as the corresponding intramolecular salt and when D is hydrogen and E is a lonely pair of electrons stands as their acid addition salt is present.

The invention thus comprises i) compounds of the formulas XlVa and XlVb

B

R

(XlVa)

and

2 2 (XlVb),

wherein R2 and R3 have the meaning given above and their pharmaceutically acceptable acid addition salts; ii) Compounds of the formulas XHIa and XHIb

N® öOR5

R OOC-CH2-CH2 (XHIa)

and wherein R2, R3, R5 and Ae have the meaning given above; and iii) compounds of formula IX

(IX),

R OOC-CH2-CH2 (Xlllb),

wherein R2 and Ae have the meaning given above and the corresponding free base.

As already stated above, the compounds according to the invention have interesting physiological activities, in particular vasodilatory activity, as will be described below.

According to the invention, the following compounds 65 are preferred:

1 a-ethyl-1β- (2'-methoxycarbonylethyl) -9-bromo-l, 2,3,4,6,7,12,12ba-octahydroindolo [2,3-a] quinolizine; la-ethyl-1β- (2'-methoxycarbonylethyl) -9-bromo-1,2,3,4,6,7,12,

654 007

4th

12bß-octahydroindolo [2,3-a] quinolizine; la-ethyl-β- (2'-carboxyethyl) -9-bromo-1,2,3,4,6,7,12,12ba-octahydro-indolo [2,3-a] quinolizine and its pharmaceutically acceptable acid addition salts; 1-ethyl-1- (2'-methoxycarbonyleth-yl) -9-bromo-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinoli-zin-5-ium- methoxide; 1-ethyl-1 - (2'methoxycarbonylethyl) -9-bromo-l, 2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-ium hydrobromide; 1-ethyl-1 - (2'methoxycarbonylethyl) -9-bromo-l, 2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-ium perchlorate; and l-ethyl-9-bromo-l, 2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-ium salts, e.g. the perchlorate.

The compounds according to the invention are produced as follows:

a) p-Halogen-anilines of the formula II

CH,

V

NH.

(VI),

optionally after conversion into an acid addition salt, with a pentanolide derivative of the formula VII

io

CH,

R2 I

"ctu-ch - ch2-O ^

: c = 0

(VII),

15

Br

// \

NH.

(II)

wherein R2 has the meaning given above, implemented the valeroyltryptamine derivative of the formula VIII obtained

are diazotized, the diazonium salt obtained is treated with a malonate of the formula III

coor4

I.

ch-chr-ch2-ch2y

I.

coor4

(III),

OH

(VIII),

wherein R4 is an alkyl group with 1 to 6 carbon atoms 30 and Y halogen, implemented in an alkaline medium, the phenylhydrazone derivative of the formula IV obtained

wherein R2 has the meaning given above, is subjected to a ring closure reaction and in the form of a 9-bromo-l-alkyl-hexahydro-indoloquinolinium salt of the formula IX

coor4

I.

c-ch2-ch2-ch2-y

II n

35

(IV),

I.

nh

-O-

Br in which R4 and Y have the meaning given above, subjected to a ring closure reaction, the 5-bromtrypt amine carboxylic acid ester of the formula V obtained

45

(IX)

product obtained, in which R2 has the meaning given above and Ae represents an acid anion, with a base and then with an acrylate of the formula X.

ch \

coor

2nd

nh.

(V),

r30-c-ch = ch, II O

(X),

hy so R3 represents a Q ^ alkyl group, or b) a 1-alkyl-hexahydro-indo-quinolinium salt of the formula XI

wherein R4 and Y have the meaning given above, either hydrolyzed in an alkaline medium and the 5-bromo-tryptamine carboxylic acid of the formula Va obtained

■ C «2—

V

NH.

(Va)

COOH

decarboxylated in an acidic medium or the ester of the general formula V hydrolyzed and decarboxylated in one step in an acidic medium, the 5-bromo-tryptamine of the formula VI obtained

(XI),

wherein R2 and A® have the meaning given above, reacted with a brominating agent, the resulting 9-bromo-1-alkyl-hexahydroindoloquinolinium salt of the above formula IX is reacted with a base and then with an acrylate of the above formula X, or c) a 1-alkyl-l-alkoxycarbonylethyl-hexahydro-indolo-quinolizinium salt of the formula XII

5

654 007

R O-C-CH

wherein R2, R3 and A® have the meaning given above, treated with a brominating agent;

the double bond between the rings C and D of the oily l-alkyl-l-alkoxycarbonylethyl-9-halogeno-he-xahydroindolo-quinolizine derivative obtained by the process a), b) or c) selectively either i) by reduction of the compound itself or ii) by reacting the former with an alcohol of the formula R5-OH, in which R5 is a CM-alkyl group, optionally the compound of the formula XHIa obtained

N® eOR5

wherein R2, R3 and R5 have the meaning given above, in an acid addition salt of the formula XHIb

(XII),

10th

15

(XHIb),

R OOC-CH2-CH2

(XHIa),

R OOC-CH2-CH2

20th

wherein R2, R3 and Ae have the meaning given above, transferred and the alkoxide or salt obtained is reduced or iii) reacted directly with an acid to form the acid addition salt of the formula XHIb and the salt is reduced;

25 and the isomer mixture obtained, containing 1-alkyl-1-alk-oxy-carbonylethyl-9-bromo-octahydroindoloquinolizine isomers of the formulas XlVa and XlVb

R OOC-CH2-CH2,

(XlVa)

and

2 ~ "2

(XlVb),

where R2 and R3 have the meaning given above, separates.

In the above formulas, R2 and R3 can be straight or branched alkyl groups of 1 to 6 carbon atoms, e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl or isohexyl groups.

The acid anion A® can be the anion of any organic or inorganic acids, especially of pharmaceutically applicable acids; as examples of suitable acids hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perhalic acids, especially perchloric acid, formic acid, acetic acid, propionic acid, glycolic acid, maleic acid, succinic acid, tartaric acid, citric acid, salicylic acid, benzoic acid, lactic acid, malic acid, tartaric acid, ascorbic acid, phenylacetic acid , An-thranilic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, p-aminosalicylic acid, embonic acid, fumaric acid, cinnamic acid, furthermore sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, halogen sulfonic acids, toluenesulfonic acid, naphthalene sulfonic acids, sulfanilic acid, aspartic acid, cycloacetic acid, aspartic acid, Glutamic acid, n-acetyl-aspartic acid or N-acetyl-glutamic acid may be mentioned.

The compounds according to the invention can be prepared in good yields from new, simple starting materials, via new simple intermediates, in a synthesis consisting of reaction steps which can be carried out easily.

The starting materials of formula II of process a) according to the invention are known and easily accessible compounds. The Ma lonsterderivate of the formula III also serving as starting materials can according to the by E. Fiso scher and H. Bergmann, Ann. 398, 120 (1913).

The diazotization of the p-bromo-anilines of the formula II can be carried out in the aqueous, advantageously concentrated solution of a strong inorganic acid, especially in concentrated aqueous hydrochloric acid, with an alkali metal nitrite, especially with sodium nitrite, at temperatures between -10 ° C. and + 5 ° C.

The solution of the diazonium salt of the compound of For-60 mei II used as starting material is then reacted with the compound of the general formula III dissolved in an inert organic solvent. As an inert organic solvent, an aliphatic alcohol, e.g. anhydrous ethanol. The reaction is advantageously carried out in an alcoholic medium in the presence of an alkaline agent, e.g. by an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide. This alkaline agent of alcoholic is expedient

654 007 6

Solution of the compound of formula III added before the solution of formula VIII, preferably in an organic solvent.

is mixed with the acidic solution of the diazonium salt. solvent dissolved or suspended and at temperatures

The resulting phenylhydrazone as a reaction product between 50 ° C and 250 ° C, advantageously at 110 ° C to 160 ° C,

dérivât of the formula IV is reacted in the form of a cis-trans isome with one of the phosphorus compounds mentioned,

get mixed. In the process according to the invention, 5. halogenated hydro

not necessary to separate these isomers at this point, especially chloroform, carbon tetrachloride, dichloro-

separate, since the ring ether or chlorobenzene is used in the subsequent reaction step. Is the

final reaction both isomers flow into the same compound to carry out this reaction selected phosphorus compound

Formula V are transferred. sig, so can an excess of this phosphorus compound

This ring closure reaction can serve as a reaction medium in an organic io.

Solvents, e.g. in an aliphatic alcohol, advantageously. After the reaction has ended, the reaction mixture is expediently mixed in n-butanol, at elevated temperature, with a base, e.g. with an alkali or alkaline earth between 40 ° and 180 ° C, optionally in the presence of a hydroxide such as sodium hydroxide, potassium hydroxide or small amounts of water. rium hydroxide, or with an alkaline alkali. The compounds of the formula is salt obtained in the above manner, e.g. Sodium carbonate or trisodium phosphate, behan-V can then be introduced into the 5-bromide in two different ways. This treatment can be carried out at room temperature or under tryptamines of the formula VI. After the egg heating, for example at 30 ° C. to 80 ° C. or with the boiling temperature method, the compounds of the formula V are first carried out at the temperature of the reaction mixture, the base in solid by alkaline hydrolysis into the corresponding 5-halogen Form, or in the form of an aqueous tryptamine-1-carboxylic acid (formula Va) and this 20 gene solution or suspension can be added.

then decarboxylated by heating in acid medium. In an advantageous manner of carrying out this ring-alkaline hydrolysis, heating in a, appropriate reaction results in phosphorus oxychloride as a phosphoric acid aqueous-alcoholic, e.g. aqueous-ethanol solution bond used and an excess of this compound used as an inorganic base, advantageously sodium or reaction medium. The reaction is carried out with the potassium hydroxide. Performed at the boiling point of the mixture and then the reaction mixture, the hydrolysis is over in a few hours - excess of the phosphorus oxychloride ends in the usual way. The subsequent decarboxylation can e.g. removed by vacuum distillation. However, it can be carried out in addition to the phosphorus oxychloride solution used by boiling the carboxylic acid in aqueous sulfuric acid solution as the phosphorus compound. e.g. a halogenated hydrocarbon, such as dichloroethane. According to the other method, the compounds of 30 or chloroform are used as the reaction medium; Formula V hydrolyzed in an acid medium in one step, the reaction is also useful in this case and at the same time decarboxylated. The boiling temperature of the reaction mixture is carried out as the acidic medium, strong inorganic acids, e.g. 10 to 20% aqueous solution From the acid addition salt of the sulfuric acid solution obtained as product, in which the mixture of general formula IX, the corresponding base can be boiled for a few hours. 35 Treatment with the alcoholic solution of an inorganic

The base obtained by either of the above methods is released.

5-Halogen-tryptamines of the formula VI are then generally used. As acid addition salts of the general formula IX, perhalogenates, e.g. Perchlorates or inorganic solvents with a 2-alkyl-pentanolide of the bromates, into consideration; however, others can also be implemented with suitable formula VII. As a solvent, preference is given to the formation of aromatic hydrocarbons, such as xylene, toluene, and addition salts formed with inorganic or organic acids, for this purpose.

or benzene. The reaction is warmed to release the bases from the acid addition salts, expediently at the boiling point of the reac-

tion mixture, carried out and is completed in about 2 to 6 hours addition salts in an inert organic solvent. 45 treated with a strong base. The released 9-bromo-l-

The reaction product of formula VIII obtained can be alkyl-hexahydroindoloquinolizine base immediately, then expediently in the same reaction mixture, which is subjected to the solution obtained with a compound of the general subsequent ring closure reaction. Formula X are implemented.

This reaction is carried out in the presence of a phosphorus compound which liberates with water to release the bases from the acid addition salts and, if appropriate, of general formula IX, advantageously dilute halogen or hydrogen halide, by heating, aqueous solutions of inorganic bases, e.g. of Al-expediently used at the boiling point of the reaction mixture metal hydroxides. Performed as an inert organic liquid. At the end of the reaction the reagent will come e.g. halogenated hydrocarbons, ion mixture preferably treated with heating with a base such as chloroform, carbon tetrachloride, dichloromethane. 551,2-dichloroethane, trichlorethylene and the like into consideration. Particularly when carrying out this ring closure reaction, dichloromethane can advantageously be used for this purpose as phosphorus compounds reacting with water. The release of the base from the salts of the general formula IX formed with oxygen and / or with halogens is expediently carried out in an inert bond of the phosphorus, e.g. Phosphorus pentachloride, Phos gas atmosphere, e.g. under argon or nitrogen, through-phosphorus trichloride, phosphorus oxychloride, also leads phosphorus pent-60. The reaction is complete at room temperature in a short time in the presence of hydrochloric acid or phosphorus trioxide.

Presence of bromine can be used. These phosphorus bonds to the organic solution obtained in the above manner are obtained in equimolecular amounts or advantageously from an acid addition salt of the general formula IX

used in excess; in the latter case, after the released base is then the compound of the general

Completion of the reaction, the excess of the phosphorus 65 formula X added. If so desired,

binding e.g. by boiling with water or alcohol, add another inert organic solvent

away. tel, e.g. tert-butanol can be added. When implementing

When this reaction is carried out, the connector is released from the salt of the general formula IX

7 654 007

Base with the acrylic acid ester of the general formula X played aluminum chloride, tin tetrachloride or boron trifluoride, the reaction time and the reaction temperature did not develop.

outgoing role; The reaction is advantageously carried out at room temperature and with reaction times of 6 hours to 6 days; it is generally in 0.5 to 4 hours, usually

worked. If necessary, the reaction can be completed in about 5 to 3 hours.

inert gas atmosphere, e.g. under argon or nitrogen, the reaction product of process a), b) or c) will be carried out. formed in the form of an inner salt which can then be converted into an acid addition salt of the general compounds (b) serving compounds of the general formula XI or formula XHIb by the starting materials of the process according to the invention. This salt can be formed from the corresponding tryptamine derivatives by formation of appropriate inorganic acids, e.g. Ha ring closure, according to which in the Hungarian patent hydrogens, such as hydrochloric acid, or perhalic acids, such as 167 366, are prepared. Perchloric acid can be used.

The bromination of the starting materials of the general form. The inner salt with XI obtained in the form of a red oil is carried out especially with elemental bromine; can, however, also directly with an aliphatic alcohol, but for this purpose also others can be used to form the general formula R5-OH, in which the abovementioned

known bromine level leading desired 9-bromo derivative, e.g. with methanol, ethanol, n-prop

agents, e.g. N-bromosuccinimide can be used. anol, isopropanol, n-butanol, etc. are treated, where-

The bromination is carried out in one, from the point of view of the alkoxy derivative which is readily crystallizable by the corresponding

Reaction inert solvent or solvent mixture of the general formula XHIa, wherein R2, R3 and R5 carried out the above. As a reaction medium, e.g. have apolar meanings given 20, which organic solvent, such as halogenated aliphatic carbon, is obtained from the alcoholic medium in crystalline form

Hydrogen oils, e.g. Chloroform, dichloromethane, etc., or separates.

polar organic solvents, e.g. organic acids, such as the compounds of general glacial acetic acid obtained in the above manner into consideration. To the solvents mentioned, my formula XHIa or XHIb, a selective - e.g. For glacial acetic acid, smaller amounts can also be subjected to a different reduction. This reduction may be due to organic solvents, e.g. Aliphatic Alko- known methods are carried out with which the hole, such as methanol are added; such mixtures can be saturated in the ring C, without also advantageously being used as the reaction medium, the halogen present on the aromatic ring. would be split off. This reduction is advantageous with a chemical reducing agent, especially with a bromination in an apolar organic solvent complex metal hydride, conveniently with a boron, e.g. in a halogenated aliphatic carbohydride, e.g. with lithium borohydride, potassium borohydride or hydrogen hydroxide, it is advantageous to carry out in counter sodium borohydride.

were from a Lewis acid, e.g. of iron (III) chloride, the reduction with borohydrides can be done in one of the

Zinc chloride, aluminum chloride, tin tetrachloride or boron 35 reaction conditions, inert solvent or suspension

trifluoride to work. diermittel, advantageously in an aliphatic alcohol or in

The bromination is advantageously carried out at room temperature in an aqueous aliphatic alcohol, e.g. performed in methanol. It is generally carried out in 0.5 to 2 hours, either in or in aqueous methanol. The bristle ended in about 1 hour. Hydride is generally used in excess, expediently in 1.5 to 7 times the molar amount in process c) according to the invention. The reactants used 1 - (2'-alkoxycarbonylethyl) -1 -alkyl- temperature and the reaction time comes no decisive-l, 2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizinium salts Importance to; these reaction conditions can be varied in the general formula XII from the corresponding dependence on the reactivity of the 1-alkyl-hexahydroindoloquinolizines used by reaction with starting materials, in general the corresponding acrylic acid esters, according to which, however, the reduction at 0 in Hungarian C, carry out the reaction described in patent 171,660, the method being prepared with stirring within 15 minutes to about 3 hours. is finished.

The bromination of the starting materials of the general form. In an advantageous embodiment of the inventive method XII, compounds of the general type are advantageously carried out using elemental bromine; for this purpose, however, other formula XHIa per se can be suspended in an aliphatic alcohol, the known suspension leading to the formation of the desired 9-bromo derivatives cooled to about 0 ° C and at this temperature-brominating agent, e.g. N-bromosuccinimide, mixed with gour with sodium borohydride in small portions, can be used with success. The reaction mixture is worked up according to customary methods. The bromination is worked up from a point of view: the excess of the reducing agent is decomposed by reaction of inert organic solvent or solution by acidifying the mixture, then the mixture of agents is carried out. For this purpose, e.g. mixed evaporated, the residue dissolved in water, the Lö-apolar organic solvents such as halogenated aliphatic made alkaline with an inert organic quench hydrocarbons, e.g. Chloroform, dichloromethane solvent extracted and the product by evaporation etc., or polar organic solvents such as glacial acetic acid, separated in the solvent.

Consider. To the solvents mentioned, e.g. to the ice- 60 The product is

sig can also receive smaller amounts of different types of organic, mostly in crystalline form. In such see solvents, e.g. aliphatic alcohols, such as meth cases, but if a mixture of the compounds of the general

anol. Such mixtures can also be used in my formulas XlVa and XlVb in powdery or oily advantageously as reaction media. Form is obtained, the compounds can crystallize

If the bromination is carried out in an apolar organic solvent from solvents customary for such purposes, e.g. from solvents, e.g. carried out in a chlorinated hydrocarbon aliphatic alcohols, such as methanol, ethanol or iso, it is advantageous, in the presence of a lepropanol, or from aliphatic ethers such as diethyl ether, Wisian acid, e.g. of ferric chloride, zinc chloride, etc., can be easily brought into crystalline form.

654 007

An isomer mixture of the corresponding compounds of the general formulas XlVa and XlVb is obtained as the product of the selective reduction. The separation of the two isomeric compounds can be carried out by the usual physical methods, e.g. by fractional crystallization from suitable organic solvents. Suitable solvents for this purpose are lower aliphatic carboxylic acid esters, lower halogenated aliphatic hydrocarbons, lower aliphatic ethers or alcohols, advantageously methanol, ethanol or isopropanol or else mixtures of the solvents mentioned.

However, the two isomeric compounds of the general formulas XlVa and XlVb can also be used because of their different physical properties, e.g. due to the different Rr values, separate from each other.

Such a suitable method is e.g. preparative layer chromatography, which takes advantage of the fact that the trans compound has a higher Rr value than the cis compound. Silica gel, e.g. Merck PF254 + 366 is used, various solvent combinations are used as eluents, e.g. 14: 2 or 14: 3 mixtures of benzene and methanol, into consideration; see. H. Halpaap: Chemical Engineering Techn. 35,488 (1963).

The separation of the eis and trans isomers of the general formulas XlVa and XlVb can also be carried out in such a way that the isomer mixture obtained as the product of the selective reduction is first hydrolyzed and then the mixture of the isomeric compounds of the general formulas present in the form of free acids Va and Vb broken down into the individual components by fractional crystallization. It has been found that these free carboxylic acids can be separated from one another particularly easily by fractional crimping. However, the release of the carboxylic acids from their esters also offers a further advantage in the production of optically active compounds: the racemic compounds containing a free carboxyl group can be broken down very easily and conveniently into their optical antipodes by forming diastereomeric salt pairs with optically active bases ( resolved).

The carboxylic acids are released from the esters of the general formulas XlVa and XlVb by the usual hydrolysis methods, e.g. by boiling with an inorganic base, e.g. with sodium hydroxide, in a suitable solvent, e.g. in ethanol.

The fractional crystallization of the mixture of the racemic or optically active ice and trans carboxylic acids can conveniently be carried out in such a way that the mixture of isomers is dissolved in a suitable organic solvent, e.g. in dimethylformamide, hot dissolves; when the solution cools, the lower-melting trans-carboxylic acid separates out in crystalline form; the crystals are separated by filtration and water is added to the filtrate, as a result of which the higher-melting cis-carboxylic acid is precipitated.

The racemic or optically active ic- or trans-carboxylic acids separated in the above manner can then be converted separately into the desired esters in a conventional manner. The esterification can be carried out, for example, by reacting the racemic or optically active carboxylic acid corresponding to the general formula XlVa or XlVb with a suitable halogenating agent and converting it to the corresponding carboxylic acid halide and then allowing it to react with the corresponding alcohol. Any racemic or optically active carboxylic acid ester of the general formulas XlVa and XlVb can be prepared in this way.

In the first step of the esterification process described above, in the reaction of the free carboxylic acid with a

Halogenating agents can e.g. Phosphorus halides, such as phosphorus oxychloride, phosphorus trichloride or phosphorus pentachloride, but especially thionyl chloride, can be used as the halogenating agent. The halogenation can optionally be carried out in an organic solvent which is inert under the reaction conditions, in the presence of an inorganic or organic base, but the reaction can also be carried out in liquid halogenating agents without additional solvents and without the addition of bases. The second step of this esterification process, the reaction of the carboxylic acid halide obtained with the alcohol containing the alkyl group of the desired ester, is expediently carried out by boiling the ester in the corresponding alcohol, optionally in the presence of an acid binder.

However, the esterification of the racemic or optically active carboxylic acids corresponding to the general formulas XlVa or XlVb can also be carried out in one step, by reacting the carboxylic acids or a salt thereof with an alkylating agent. Particularly suitable salts of the carboxylic acids are alkali metal salts, e.g. the sodium salts or potassium salts. Alkyl halides, e.g. Alkyl bromides, but especially alkyl iodides. The alkyl group of the alkyl halide to be used can be a straight or branched alkyl group with 1 to 6 carbon atoms, especially a primary or secondary alkyl group, e.g. be a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, n-pentyl, iso-pentyl, n-hexyl or isohexyl group. As advantageous alkylating agents e.g. Methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, isopropyl bromide, isopropyl iodide, sec-butyl iodide, sec-butyl bromide, etc. may be mentioned. The alkylation can be carried out in a dipolar aprotic solvent, e.g. in hexamethylphosphoric acid amide or in dimethylformamide. If a free carboxylic acid is used as the starting compound, the reaction is carried out in the presence of an inorganic base, e.g. of aqueous potassium or sodium hydroxide solution, of sodium hydride or especially of potassium carbonate. However, it is also possible first to convert the free carboxylic acid into the corresponding salt by reaction with such a base and then to react this salt with the alkylating agent.

The racemic or optically active la-alkyl-lß-alkoxycar-bonylethyl-9-bromo-12baH-octahydroindoloquinolizine of the general formula XlVa obtained by one of the methods described above is then used as the starting compound in the next reaction step of the process according to the invention; the isomeric compound of the general formula XIVb can be returned to the corresponding hexahydrover compound of the general formula XHIb or XHIa by oxidation with an alkali metal bichromate and then used again as an intermediate in the process according to the invention. The details of this method are described in Applicant's HU Patent No. 178,701.

The reaction mixtures obtained in the individual reaction steps of the process according to the invention can be worked up by methods known per se and customary in such cases. Depending on the nature of the product, the solvent present, etc., the intermediate or end products can be isolated by filtering off the precipitated product or, if the desired product remains dissolved in the reaction mixture, by evaporating the solution, optionally under reduced pressure, and by recrystallization be cleaned from suitable inert organic solvents. The solvents to be used for this purpose may vary depending on

8th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

the solubility ratios and crystallization properties of the products. When working up the reaction mixtures, one can also proceed in such a way that the desired product is mixed with a suitable inert organic solvent, e.g. with dichloromethane, di-chloroethane, etc., extracted from the reaction mixture, the organic solution of the product obtained is dried and evaporated in the customary manner and the residue is crystallized, if appropriate, from suitable solvents. If necessary, the product can also be added by adding a suitable inert organic solvent, e.g. of ether, precipitate from the reaction mixture and isolate by filtration. If desired, the racemic or optically active compounds obtained can be treated by further suitable treatment methods, e.g. by recrystallization, can be further purified.

The products obtained by the process according to the invention can also be purified by preparative layer chromatography. For this purpose, silica gel, e.g. Merck PF254 + 366 silica gel, and any suitable solvent combination can be used as the eluent.

The racemic or optically active compounds of the general formula Va, VI, VIII, IX, XI, XII, XHIa, Xlllb, XlVa or XlVb produced by the process according to the invention can, if desired, be converted into pharmaceutically acceptable acid addition salts by reaction with acids suitable for such purposes. Suitable acids for such purposes are e.g. inorganic acids such as hydrogen halide e.g. Hydrochloric acid, hydrogen bromide, etc., furthermore sulfuric acid, phosphoric acid, per-halogen acids, such as perchloric acid, etc., and also organic carboxylic acids, such as formic acid, acetic acid, propionic acid, oxalic acid, glycolic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, ascorbic acid, citric acid, malic acid , Salicylic acid, lactic acid, benzoic acid or cinnamic acid, sulfonic acids, such as methanesulfonic acid, p-toluenesulfonic acid or cyclohexanesulfonic acid, or also amino acids, such as aspartic acid, glutamic acid, N-acetyl-aspartic acid, N-acetyl-glutamic acid, etc., into consideration.

The salt formation can suitably be carried out in a solvent which is inert under the reaction conditions, advantageously in an aliphatic alcohol, e.g. in methanol, in such a way that the base of the general formula Va, VI, Vili, IX, XI, XII, XHIa, Xlllb, XlVa or XlVb is dissolved in this solvent and then the acid selected for salt formation is added in such an amount that the mixture should show a weakly acidic reaction (about pH = 6). The salt of the compound of the general formula Va, VI, Vili, IX, XI, XII, XHIa, Xlllb, XlVa or XlVb obtained in this way separates from the reaction mixture or can be obtained by adding a suitable organic solvent, e.g. of ether to be felled.

Since the compounds of general formula I according to the invention contain asymmetric carbon atoms, the compounds obtained in racemic form can be broken down into optical antipodes. The present invention also extends to the preparation of the optically active antipodes of the compounds of the general formula I. The resolvation, which can be carried out by the customary methods, can form the last step of the process according to the invention; however, one can also use an optically active starting compound IX, or resolve any racemic intermediate of the process according to the invention and carry out the further steps of the process with optically active intermediates. If desired, they can be obtained in an optically active form

The products of the process can also be racemized according to methods known per se.

The compounds of the general formula I can be prepared in high yields in 5 pure and easily identifiable form by the process according to the invention; the results of the elementary analysis show good agreement with the calculated values and the chemical composition and structure of the products represented by the general formula I is also determined by the results of the in-

10 infrared spectroscopy, nuclear magnetic resonance spectroscopy and mass spectroscopy clearly confirmed.

The intermediates of the process according to the invention of the general formulas IV, V, Va, VI, VIII, XI and XII are new compounds 15 which have not previously been described in the literature; the intermediates mentioned are themselves biologically active and show valuable pharmacological properties.

The products according to the invention were subjected to pharmacological tests. It has been found that the compounds of the general formulas XlVb, Xlllb, XlVa and IX show significant therapeutic effects.

The blood circulation tests were carried out on dogs anesthetized with chloralose urethane. The arterial blood pressure, the pulse number, the blood flow 25 in the arteria femoralis and in the arteria carotis interna, and the vascular resistance of the two blood vessel areas (blood pressure divided by the blood flow) were measured or calculated.

The compounds to be examined were administered intravenously, 30 in doses of 1 mg / kg body weight. Each compound was tested in 5 to 6 parallel tests.

The results were summarized in Tables 1 to 4 below. The abbreviations used in the tables:

35 M ABP = mean arterial blood pressure HR = pulse number

CBF = blood flow in the internal carotid artery CVR = vascular resistance in the internal carotid artery FBF = blood flow in the arteria femoralis 40 FVR = vascular resistance in the femoral artery

45

Table 1

Effect of la-ethyl-1β- (2'-methoxycarbonyl-ethyl) -9-bromo-l, 2,3,4,6,7,12,12bß-octahydro-indolo [2,3-a] quinolizine 50 on the bloodstream

(Average ± deviation from average)

Control treated

55 MABPmmHg

110

5.2

84.2

±

5.5

%

-

23

HR min-1

187

±

17th

204

±

16

%

+

9.8

CBFmLmin-1

90

±

13

93

±

13

60%

+

5.7

CVR

mmHg.min.ml_1

1.4

±

0.3

1.0

±

0.2

%

-

25th

FBF ml.min "1

31.7

±

4.8

72.5

±

11

65%

+

138

FVR

mmHg.min.ml_1

0.89

±

0.2

0.38

±

0.1

%

-

53

654 007

10th

Table 2

Effect of l-ethyl-l- (2'-methoxycarbonyl-ethyl) -9-bromo-l, 2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-iumperchlorate on the bloodstream

(Average ± deviation from average)

Control Treat1 *

MABPmmHg 144 ± 8.3 103 ±

%

%

HR min-1%

CBFml.min-1

%

CVR

mmHg.min.ml-1%

FBF ml.min "1%

FVR

mmHg.min.ml_ 1 5.7 Table 3

It can be seen from the data in the tables above that the new compounds on anesthetized dogs in intravenous doses of 1 mg / kg body weight only slightly reduce blood pressure and hardly influence the number of pulses. Their outstanding effect is the reduction of vascular resistance in the extremities (blood vessel widening activity). The effect is particularly important for the compounds in Tables 1, 2 and 3, where the vessel expansion is 50 to 70%. At the same time, blood circulation increases by 90 to 140%. A slight vasodilation (10 to 25%) was also caused by these connections in the area of the carotid artery.

For comparison, we give the results of blood circulation tests with vincamine below.

15

Table 5

HR min 1

%

CBF ml.i

%

CVR

mmHg.min.ml_I 2.6 ± 0.3%

FBF ml.min'1%

FVR

mmHg.min.ml ~ 1

%

Table 4

Effect of l-ethyl-9-bromo-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-ium perchlorate on the blood circulation

(Average ± deviation from average)

Control treated

137

148

Effect of vincamine on blood circulation

20 (average ± deviation from average)

control

Treated

MABP mmHg

131.2

111.8

%

-14.7 ± 1.8

25 HR min-1

181.2

164.8

%

-9.1 ± 2.6

CBFmLmin-1

39.2

40.8

%

+ 4.8 ± 0.8

CVR mmHg.min.ml "1

3.25

2.94

30%

-9.5 ± 2.4

FBF ml.min_1

35.9

42.78

%

+ 19.2 ± 3.5

FVR mmHg.min.ml ~ 1

3.65

2.61

%

-28.5 ± 5.4

MABP mmHg

%

HR min-1%

CBF ml.min-1%

CVR

mmHg.min.ml "1

%

FBFmLmin.-1

%

FVR

mmHg.min.ml_I%

143 159 62.8

± 6.4 ± 22.0 ± 15.0

2.8 ± 0.6 37.6 ± 9.7

5.3 ± 1.7

± 5.6

- 4.2 ± 18.0

- 7.1 62.4 ± 15.0

0

2.8 ± 0.7 0

47.4 ± 14.0 + 26

4.9

± 2.2 - 7.5

35

The invention further encompasses those embodiments of the process in which any of the intermediates defined above is used as the starting material and only the reaction steps still required until the end product is produced, or in which the process in the production of one of the new ones mentioned above Intermediate products is canceled.

It should also be mentioned that in the preparation of the end products of the general formula I, the intermediate products described above do not have to be isolated in most cases after the individual reaction steps in most cases, but in the crude state, often even in situ in the obtained Reaction mixture can be implemented further.

The preparation of individual starting materials of the so examples are described in GB-PS 2 106 505.

The process according to the invention is illustrated in more detail by the examples below; however, the invention is in no way limited to the content of these examples.

55

example 1

l-ethyl-9-bromo-l, 2,3,4,6,7-hexahydro-12H-indolo [2,3-aJchi-nolizin-5-ium perchlorate

0.48 g (2.0 mmol) of 5-bromo-tryptamine and 0.30 g of fio (2.3 mmol) of 2-ethyl-pentanolide are dissolved in 5 ml of abs. Xylene dissolved and the solution boiled under reflux for 4 hours. The reaction mixture is evaporated in vacuo, the residue is triturated twice with 3 ml of petroleum ether and dried in a desiccator. 0.59 g of N- (a-ethyl-5-hydroxy-va-65 leroyl) -5-bromo-tryptamine (80% of theory) are obtained. IR (in KBr): 3320 (NH, OH broad), 1640 (acid amide CO) cm-1.

The 0.59 g of N- (a-ethyl-ö-hydroxy-valeroyl) -5-bromo-tryptamine obtained are washed with 5 ml of phosphorus

11

654 007

oxychloride added. The mixture is boiled under reflux for 6 hours, then the excess phosphorus oxychloride is distilled off in vacuo, 5 ml of 4 N aqueous sodium hydroxide solution are added to the residue while cooling with ice, and the mixture is stirred at room temperature for 15 minutes. The organic phase is separated off, the aqueous phase is extracted three times with 3 ml of dichloroethane each time, the organic phases are combined, dried with anhydrous magnesium sulfate and filtered off. The solvent is distilled off from the filtrate in vacuo, the oily residue (0.65 g) is dissolved in 3 ml of methanol and the solution is adjusted to pH = 6 by the addition of aqueous 70% perchloric acid solution. The precipitated crystals are separated by filtration, washed with cold methanol and dried. In this way, 0.40 g of l-ethyl-9-bromo-l, 2,3,4,6,7-he-xahydro-12H-indolo [2,3-a] quinolizine-5-ium perchlorate (calculated on the 5-bromo-tryptamine: 46% of theory);

F .: 233-234 ° C (from methanol).

IR (in KBr): 3250 (indole-NH), 1622.1545 (C = H) cm "1. Analysis for C] 7H2oN2ClBrC> 4 (mol. Weight: 431.72):

calculated: C 47.29% H 4.67% N6.49%;

found: C 47.08% H 4.55% N 6.36%.

Example 2

l-ethyl-l- (2'-methoxycarbonylethyl) -9-bromo-l, 2,3,4,6,7-he-xahyd.ro-7aH-indolo [2,3-aquinolizine-5-ium methoxide

7.00 g (16.2 mmol) l-ethyl-9-bromo-l, 2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-ium perchlorate are dissolved in 160 ml dichloromethane, the solution is shaken well in a separating funnel with the mixture of 28 ml 10% aqueous sodium hydroxide solution and 111 ml water, the organic phase is separated off and dried with anhydrous potassium carbonate. The dichloromethane solution of the released base obtained in this way is then mixed with 8.90 g (103.5 mmol) of methyl acrylate. The mixture is left to stand at room temperature for two days, then the solvent is distilled off in vacuo and the oily residue is crystallized from methanol. 4.70 g of 1-ethyl-1- (2'-methoxycarbonyleth-yl) -9-bromo-l, 2,3,4,6,7-hexahydro-7aH-indolo [2,3- a] quinoli-zin-5-ium methoxide (64.5% of theory) in the form of orange-yellow crystals;

F. 140-142 ° C (from methanol). IR (in KBr):

1730 (-COOCH3), 1560, 1480 (C = N) cm "1.

Ms m / e (%):

420 (8.5), 419 (9.3), 418 (M +, 11), 417 (8.8), 405 (0.8), 403 (1.1), 401 (0.6), 389 (1.7), 387 (2.5), 385 (2.9), 383 (1.9), 347 (9.9), 345 (13), 332 (43), 317 (99), 315 (100), 303 (11), 301 (12), 250 (5.8), 249 (6.0), 248 (6.0), 247 (5.5).

Under the conditions of the mass spectrographic examination, methanol and a bromine-containing compound (molecular weight: 418) can be detected in the vapor space of the sample.

H-NMR (CDC13): 6 = 7.47 - 7.05 (3H, m, aromatic protons), 3.55 (6H, s, -COOCH3, -OCH3), 0.82 (3H, t, - CH2CH3).

0.1 g of the above product is suspended in 1 ml of methanol and 70% aqueous perchloric acid is added to the suspension up to pH = 6. The crystals obtained are separated by filtration, washed with a little methanol and dried. 0.095 g of l-ethyl-l- (2'-methoxycar-bonylethyl) -9-bromo-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5 -ium perchlorate obtained;

Mp 221-222 ° C (from methanol).

IR (in KBr): 3300 (indole-NH), 1718 (-COOCH3), 1620 and 1538 (C = N) cm_1.

Example 3

l-ethyl-9-bromo-l, 2,3,4,6,7-hexahydro-12H-indolo [2,3-a] chi-nolizine-5-ium perchlorate

12.00 g (34 mmol) of l-ethyl-l, 2,3,4,6,7-hexahydro-12H-5 indolo [2,3-a] quinolizine-5-ium perchlorate are dissolved in 276 ml of dichloromethane and 48 ml of 10% aqueous sodium hydroxide solution and 192 ml of water are added to the solution. The mixture is shaken vigorously in a separating funnel (pH = 11). The organic phase is then separated off, dried with solid potassium carbonate, filtered and the filtrate is evaporated to dryness in vacuo. The evaporation residue is dissolved in methanol and acidified to pH = 6 with hydrochloric acid dissolved in methanol. The solvent is distilled off in vacuo, the oil obtained as a residue is dissolved in 70 ml of glacial acetic acid, the solution is mixed with 5 ml of methanol and the solution of 6.55 g (41 mmol) of bromine in 30 ml is then stirred at room temperature Glacial acetic acid slowly added. The reaction is complete after about an hour and the product 20 is deposited in an oily form on the vessel wall. The glacial acetic acid is decanted, the remaining oil is dissolved in 30 ml of warm methanol and the solution is mixed with 2.92 ml of 70% aqueous perchloric acid solution (up to pH = 5). The precipitated product is separated by filtration, washed with a little cold methanol and dried. In this way, 9.02 g of l-ethyl-9-bromo-l, 2,3,4,6,7-hexahydro-12H-in-dolo [2,3-a] quinolizine-5-ium perchlorate are obtained receive.

The glacial acetic acid solution decanted from the oily crude product is evaporated in vacuo, the residue is dissolved in 10 ml of 30 warm methanol and mixed with 70% aqueous perchloric acid solution up to pH = 5. The precipitated product is filtered off, washed with cold methanol and dried. In this way, a further 1.47 g of the above product are obtained, so that the overall yield is 10.49 g (71.4% of 35 th.).

F .: 233-234 ° C.

IR (in KBr): 3250 (indole-NH), 1622.1545 (C = H) cm- '. Analysis for C17H2oN2ClBr04 (mol. Weight: 431.72):

calculated: € 47.29% H 4.67% N6.49%;

40 found: C 47.08% H4.55% N6.36%.

Example 4

1-Â-ethyl-1 - (2'-methoxycarbonylethyl) -9-bromo-l, 2,3,4,6,7-he-45 xahydro-12H-indolo [2,3-a] quinolizine-5-ium -methoxide

4.39 g (10 mmol) of l-ethyl (2'-methoxycarbonylethyl) -1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-ium perchlorate are shaken with 5 ml of 10% aqueous ammonium hydroxide solution and 50 ml of dichloromethane, then the phases are separated from one another. The organic phase is dried with 10 g of solid anhydrous sodium sulfate, filtered, the filtrate is concentrated to about 40 ml and 0.1 g of anhydrous iron (III) chloride is added to the residue. 2.08 g (13 mmol), 0.67 ml) of elemental bromine are added dropwise to this mixture at 25 ° C. with vigorous stirring in 5 minutes. The reaction mixture is stirred at room temperature for 2 hours, then made alkaline with 10 ml of 10% aqueous ammonium hydroxide solution and the precipitated iron hydroxide is filtered off. 60 The organic phase is separated from the filtrate, dried with 10 g of solid, anhydrous sodium sulfate, filtered off and the filtrate is evaporated to an oil. The oil obtained as a residue is mixed with 10 ml of methanol, whereupon the product precipitates in the form of 65 crystals containing crystal methanol. In this way, 3.81 g of 1-ethyl-l- (2'-methoxycarbonylethyl) -9-bromo-l, 2,3,4,6,7-hexa-hydro-12H-indolo [2,3- a] quinolizine-5-ium methoxide (85% of theory) was obtained;

654007 12

F. 140-142 ° C. see and dried. In this way, 0.095 g

'H-NMR (in CDCI3): 8 = 0.8 (t, 3H, -CH2CH3), 7.6 (2H, Ar l-ethyl-1- (2'-methoxycarbonylethyl) -9-bromo-1,2 , 3,4,6,7-he-

10-11H), 8.1 (1H, Ar 8H) ppm. xahydro-12H-indolo [2,3-a] quinolizine-5-ium perchlorate obtained;

Example 5 5 F. 221-222 ° C (from methanol).

l-Àthyl-l- (2'-methoxycarbonylâthyl) -9-bromo-l, 2,3,4,6,7-he-IR (in KBr): 3300 (indole-NH), 1718 (-COOCH3), 1620 and xahydro-12H-indolo [2,3-a] quinolizine-5-ium methoxide 1538 (C = N) cm _ 1.

4.39 g (10 mmol) l-ethyl-l- (2'-methoxycarbonylethyl) -

1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-ium- Example 8

Perchlorate are mixed with 5 ml of 10% aqueous ammonium- \ o (±) -la-ethyl-lß- (2'-methoxycarbonylethyl) -9-bromo-

hydroxide solution and 50 ml of dichloromethane shaken. The 1,2,3,4,6,7,12,12ba-octahydroindolo [2,3-a quinolizine and

Phases are separated, the organic phase with 10 gfe- (±) -la-ethyl-lß- (2'-methoxycarbonylethyl) -9-bromo-

stem, anhydrous sodium sulfate dried and filtered. 1,2,3,4,6,7,12,12bß-octahydroindolo [2,3-aquinolizine

0.5 g of dry hydrochloric acid gas are passed into the filtrate, 6.50 g (14.4 mmol) of l-ethyl-l- (2'-methoxycarbonylethyl) -

then 50 ml of glacial acetic acid are added and the dichloro-15 9-bromo-l, 2,3,4,6,7-hexahydro-7aH-indolo [2,3-a] quinolizine

than is evaporated in vacuo. 5-ium methoxide in 20 ml of 1: 1 mixture of dichloro-

Dissolved 0.67 ml (2.08 g, 13 mmol) of methane and methanol at 25 ° C. with vigorous stirring and the solution was added dropwise at 0 ° C. under elemental bromine. The reaction stirring with 0.55 g of sodium borohydride mixed in small portions is stirred at room temperature for 3 hours, which exposes. After the end of the addition, the mixture of separated product is filtered off and the remaining 20 stirring is continued for 30 minutes, then with acetic acid to pH

bene acetic acid from the product remaining on the filter = 6 acidified and evaporated to dryness in vacuo,

thoroughly vacuumed. The product, which is still moist, is washed with 5% aqueous sodium carbonate.

40 ml of dichloromethane suspended, the thin suspension made alkaline with solution up to pH = 8-9 and the resultant

14 ml of 10% aqueous ammonium hydroxide solution, alkali solution extracted with dichloromethane. The organic phase made lisch; the phases are separated, the organic 25 is separated off, dried with anhydrous magnesium sulfate.

Phase dried with 10 g of solid anhydrous sodium sulfate, filtered off and the solvent in vacuo from the filtrate

net, filtered off and the filtrate was distilled off in vacuo to an oily residue. The oil obtained as a residue (6.10 g)

narrowed. The oily product is mixed with 10 ml of methanol, and is prepared by preparative thin layer chromatography (on Si

whereupon the product in the form of crystal-methanol licagel KG-PF254 + 366 Merck, with a 14: 3 mixture of crystals contained. 30 benzene and methanol) are broken down into the components; the 12bß-

3.15 g of l-ethyl-l- (2'-methoxycarbonylethyl) -9-bromo isomer has a higher Rr value than that for further syn-

1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-iumethese required 12ba compound. By eluting with a

get methoxide (70% of theory); nem 10: 1 mixture of dichloromethane and methanol

F. 140-142 ° C. The NMR spectrum of the product is 2.70 g (±) -la-ethyl-lß- (2'-methoxycarbonylethyl) -9-bromo-

identical to that given in Example 4. 35 1,2,3,4,6,7,12,12ba-octahydroindolo [2,3-a] quinolizine (44.5%

d. Th.) Received;

Example 6 F. 166-168 ° C (from methanol).

l-ethyl-l- (2'-methoxycarbonylethyl) -9-bromo-l, 2,3,4,6,7-he- IR (in KBr): 3380 (indole-NH), 2800,2750 (Bohlmann ' xahydro-12H-indolo [2,3-a] quinolizine-5-iwn-hydrobromide bands), 1720 (-COOCH3) cm ~ 1.

4.39 g (10 mmol) l-ethyl-l- (2'-methoxycarbonylethyl) - 40 Ms m / e (%):

l, 2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizin-5-ium-420 (81.6), 418 (M +, 81.2), 405 (8, 1), 403 (8.1), 389 (9.5),

Perchlorate are mixed with 5 ml of 10% aqueous ammonium 387 (5.4), 347 (95.5), 345 (100), 317 (2.6), 315 (2.6), 277 (28.9) ,

hydroxide solution and 50 ml of dichloromethane shaken. The 275 (30.7), 250 (27.9), 248 (31.6), 168 (19.5).

Phases are separated, the organic phase with 10 g fe- 'H-NMR (DMSO-d6, CDC13): 8 = 7.62 - 7.12 (3H, m, aro-

stem, anhydrous sodium sulfate dried and filtered. 45 matical protons), 3.58 (3H, s, -COOCH3), 3.50 (1H, s, 12

The filtrate is mixed with 50 ml of glacial acetic acid and the dichloro-bH), 1.11 (3H, t, -CH2CH3).

methane is evaporated in vacuo. 0.1 g of the above 12ba derivative are suspended in 1 ml of methanol, 0.67 ml (13 mmol) at 25 ° C. with vigorous stirring and until pH = 6 with methanolic hydrochloric acid

208 g) elemental bromine added dropwise. That reacts. The crystals obtained are filtered off, stirred with a little ion mixture at room temperature for 3 hours, then washed with methanol and dried. The precipitated yellow, crystalline product is filtered off on this and dried 0.095 g (±) -1 a-ethyl-1 ß- (2'-methoxycarbonylethyl) -9-

net. In this way, 4.5 g of 1-ethyl 1- (2'-methoxy-bromo-l, 2,3,4,6,7,12,12ba-octahydroindolo [2,3-a] quinolizine-

carbonylethyl) -9-bromo-l, 2,3,4,6,7-hexahydro-12H-indo-5-ium hydrochloride;

lo [2,3-a] quinolizine-5-ium hydrobromide (90% of theory) - F. 223-225 ° C.

hold; 55

M. 127-128 ° C. The NMR spectrum of the product shows From the in the thin-layer chromatographic separation

the values given in example 4. other fraction obtained (with a higher Rr value)

2.02 g (±) -la-ethyl-lß- (2'-meth-

Example 7 oxycarbonylethyl) -9-bromo-1,2,3,4,6,7,12,12bß-octahydroin-

l-ethyl-l- (2'-methoxycarbonylethyl) -9-bromo-l, 2,3,4,6,7-he-6 "dolo [2,3-a] quinolizine (33.3% of theory .) receive;

xahydro-12H-indolo [2,3-a] quinolizine-5-ium perchlorate F. 140-142 ° C (from methanol).

0.1 g l-ethyl-l- (2'-methoxycarbonylethyl) -9-bromo-IR (in KBr): 3300 (indole-NH), 2830.2750 (Bohlmann's l, 2,3,4,6 , 7-hexahydro-12H-indolo [2,3-a] quinolizine-5-ium bands), 1710 (-COOCH3) cm "1.

methoxide (produced according to Example 4) is dissolved in 1 ml of methanol Ms m / e (%):

suspended and the suspension by the addition of 65 420 (100), 418 (M +, 100), 405 (11.2), 403 (11.9), 389

70% aqueous perchloric acid solution to pH = 6 - (11.1), 387 (9.9), 347 (90.2), 345 (90.8), 317 (8.3), 315 (7.4) ,

poses. The product precipitating in crystalline form 277 (26.5), 275 (27.5), 250 (25.6), 248 (27.1), 168 (15).

is separated off by filtration, washed with a little methanol. H NMR (CDCl 3): 8 = 9.00 (1H, s, indole proton) 7.62-7.10

(3H, m, aromat, protons) 3.80 (3H, s, -COOCH3) 3.33 (IH, s, 12bH) 0.68 (3H, t, -CH2ÇH3).

Example 9

(±) -la-ethyl-l $ - (2'-methoxycarbonyl-ethyl) -9-bromo-l, 2,3,4,6,7,12,12ba-octahydroindolo [2,3-a] quinolizine

1.1g (2.63 mmol) according to the example! 1 isomer mixture prepared is dissolved warm in a mixture of 5 ml of ethanol and 0.3 ml of water, 0.35 g of solid sodium hydroxide are added and the mixture is boiled under reflux for one hour. The solvent is then distilled off in vacuo, the residue is dissolved in 13 ml of water and the solution is acidified to pH = 6 with 10% aqueous acetic acid solution. The precipitated mixture of the isomeric carboxylic acids is separated off by filtration, washed with water, dried and extracted from 10 ml of abs. Recrystallized dimethylformamide. In this way, there are 0.35 g (±) -l a-ethyl-lß- (2'-carb-oxyethyl) -9-bromo-l, 2,3,4,6,7,12,12ba-octahydroindolo [2,3-a] quinolizine (33% of theory) obtained;

F.214-215 "C.

IR (in KBr): 3420.3100 (-OH, -NH-), 1680 (acid-CO)

cm

-1

The 0.35 g product obtained in the above manner is suspended in 10 ml dichloromethane and an excess of diazomethane dissolved in dichloromethane is added to the suspension. The solution obtained after the end of the reaction is evaporated to dryness and the residue is crystallized from methanol. 0.3 g of (±) -la-ethyl-lß- (2'-methoxycarbonylethyl) -9-bromo-1,2,3,4,6,7,12,12ba-octa-hydroindolo [2,3 -a] quinolizine obtained;

13 654 007

Mp 166-168 ° C (from methanol). The physical data of this product are the same as those of the corresponding compound prepared according to Example 8.

5 Example 10

(-) -l (S), 12b (S) -9-bromo-l-ethyl-l- (2'-methoxycarbonyl-ethyl) -1,2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizine-di-benzoyl-D-tartrate

1.4 g (0.32 mmol) (±) -1 a-ethyl-1β- (2'-methoxycarbonyl-10 ethyl) -9-bromo-l, 2,3,4,6,7,12, 12ba-octahydroindolo [2,3-a] quinolizine are dissolved in 3 ml dichloromethane and mixed with the solution of 1.19 g D-dibenzoyl tartaric acid in 7 ml dichloromethane. The mixture is heated to boiling, then left to stand for one hour at room temperature and then for 12 hours at +10 ° C. The product which has separated out is filtered off, washed with dichloromethane and dried. 0.82 g of (-) -I (S), 12b (S) -l-ethyl-l- (2'-methoxycarbonylethyl-9-bromo-l, 2,3,4,6,7, 12,12b-octahydroindo-lo [2,3-a] quinolizine-D-dibenzoyl tartrate (26% of theory), he-20;

Mp 153-154 ° C; [a] ^ = -98 ° (c = 1, dimethylformamide). 'H NMR (CDC13): 8 = 0.9 ppm (3H, t, -CH2CH3), 4.1 ppm (1H, s, 12b-H), 7.3-7.6 ppm (2H, Ar, Ar 10-11 H), 25 8.2-8.4 ppm (1H, Ar 9-H).

The base released from the above salt shows the optical rotation value [a] ^ = -101.9 ° (c = 0.726, dichloromethane).

30th

C.

Claims (7)

654 007 2nd PATENT CLAIMS 1. Compounds of Formula I (I), where R2 is an alkyl group with 1 to 6 carbon atoms and B is hydrogen or a group of the formula R3OOC-CH2CH2-, where R3 is an alkyl group with 1 to 6 carbon atoms and either D and E together represent a carbon-nitrogen bond, where10 15 in which positively charged nitrogen is stabilized by an acid anion or the OR5 anion, where R5 represents an alkyl group having 1 to 6 carbon atoms or, if B does not represent hydrogen, D can also represent hydrogen and E represents a lone pair of electrons; with the proviso that when B is hydrogen, D and E together are a carbon-nitrogen bond, the positively charged nitrogen atom of which is stabilized by an acid anion and R3 is hydrogen when D is a hydrogen atom and E is an electron pair; wherein the compounds of formula I, when B is hydrogen, as a free base, when B is not hydrogen and D and E together represent a carbon-nitrogen bond, as the corresponding intramolecular salt and when D is hydrogen and E is a lonely pair of electrons stands as their acid addition salt is present. 2. Compounds according to claim 1 of the formula XlVa or XlVb r "ooc-ch2-ch2 (XlVa) or * 2 2 (XlVb), wherein R2 and R3 have the meaning given in claim 1 and their pharmaceutically acceptable acid addition salts. 3. la-ethyl-1β- (2'-methoxycarbonylethyl) -9-bromo-1,2,3,4,6,7,12,12ba-octahydromdolo [2,3-a] quinolizine, 1 a-ethyl -lß- (2'-methoxycarbonylethyl) -9-bromo-l, 2,3,4,6,7,12, 12bß-octahydroindolo [2,3-a] quinolizine, la-ethyl-lß- (2'-carb-oxyethyl) -9-bromo-1,2,3,4,6,7,12,12ba-octahydroindolo- [ 2,3-a] - quinolizine or its pharmaceutically acceptable acid addition salts, as compounds according to claim 1. 35 4. Compounds according to claim 1 of the formula XHIa or XHIb eOR5 R OOC-CH2-CH2 (XHIa) or R OOC-CH2-CH2 (Xlllb), wherein R2, R3 and R5 have the meaning given in claim 1 and Ae stands for an anion. 5. l-ethyl-l- (2'-methoxycarbonylethyl) -9-bromo- 1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-ium methoxide, l-ethyl-l- (2'-methoxycarbonylethyl) -9-bromo-1 , 2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-ium hydrobromide or l-ethyl-l- (2'-methoxycarbonylethyl) -9-bromo-1, 2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-ium perchlorate, as a compound according to claim 4. 6. Compounds according to claim 1 of formula IX A® means an acid anion or the free base of this verso bond. 7. l-Ethyl-9-bromo-1,2,3,4,6,7-hexahydro-12H-indolo- [2,3-a] -quinolizine-5-ium salt, in particular l-ethyl-9 -bromo-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-ium perchlorate, as a compound according to claim 6. 55 8. Process for the preparation of a compound of Formula IX according to claim 6, characterized in that a compound of formula VIII 60 (IX), wherein R2 has the meaning given in claim 1 and 65 (VIII), 3rd 654 007 wherein R2 has the meaning given in claim 1, is subjected to a ring closure reaction. 9. A process for the preparation of a compound of formula IX according to claim 6, characterized in that a compound of formula XI 10th (XI), wherein R2 has the meaning given in claim 1 and Ae stands for an acid anion, brominated. 20th